Transfusion therapy, the cornerstone of the treatment of thalassemia major, dramatically improves the quality and length of life of affected patients. However, iron overload is an inevitable, life-threatening complication of long-term administration of red cells. Iron chelation therapy with deferoxamine removes excessive iron, but the need for parenteral administration of the chelator, drug-related side effects and high cost lead to poor compliance and numerous treatment failures. An alternative approach to removing transfusional iron with chelators is to decrease the rate of iron accumulation by modifying the approach to transfusion therapy. Based on our success in applying partial exchange transfusion by erythrocytapheresis (PET-E) to the prevention of recurrent stroke in sickle cell disease, the current study has been developed with the primary objective of defining the role of PET-E in reducing the rate of transfusional iron accumulation in patients with thalassemia major. The specific aims of the study are (1) to compare net red blood cell requirements (and therefore the rate of iron loading) with PET-E and simple transfusion; (2) to determine the mechanism(s) for a reduction in net red cell loading with PET-E; and (3) to determine the incremental cost effectiveness of PET-E versus simple transfusion. Using a crossover study design, fifteen patients will be treated for 18 months with PETE-E and simple transfusion will be performed every three weeks to maintain the hemoglobin level above 9-10.5 g/dl. To address the first specific aim of comparing the effects of the two transfusion programs on transfusional iron accumulation, net rate of red cell loading will be compared with PET-E and simple transfusion. To address the second specific aim of determining the basis for reduced net red cell loading with PET-E in comparison with simple transfusion, differences in red cell age will be determined by density gradient separation, and the rate of endogenous erythropoiesis will be assessed by measurement of circulating F-cells and serum transferrin receptor levels. To address the third specific aim regarding cost effectiveness, investigators from the Centers for Outcome Research will analyze the incremental dollars per life-year saved with endpoints at the end of the study period and 25 years later. The successful application of PET-E to the management of thalassemia major will not only reduce the rate of iron loading and the need for chelation therapy in this hemoglobinopathy but will also improve the overall care and long-term outlook for all patients with transfusion-dependent hematologic disorders.